glutathione peroxidase

Glutathione Peroxidase (GSH-Px; EC 1.11.1.9), a member of the peroxidase family, catalyzes the oxidation of reduced glutathione (GSH) to oxidized glutathione (GSSG) by forming a disulfide bridge, concurrently reducing hydrogen peroxide or lipid peroxides to water. This enzyme serves as a potent antioxidant, protecting against oxidative stress [1].

GPX4 24, a derivative of (1S,3R)-RSL3, acts as a potent inhibitor of glutathione peroxidase 4 (GPX4) through covalent binding in a concentration-dependent manner within 4T1 murine mammary carcinoma cells. This compound effectively induces ferroptosis in GPX4-dependent HT-1080 fibrosarcoma cells with an EC50 value of 0.16 µM. Additionally, at a dose of 200 mg/kg, GPX4 24 elevates malondialdehyde (MDA) levels in both kidney and plasma of mice, highlighting its impact on lipid peroxidation.

JKE-1674 is an inhibitor of glutathione peroxidase 4 (GPX4). JKE-1674 is an active metabolite of the GPX4 inhibitor ML-210.

RSL3 (RSL3 1S) is an inhibitor of GPX4, and inhibits system xc- that blocks GSH synthesis (IC50=100 nM). RSL3 is a VDAC-independent activator of ferroptosis that is selective for tumor cells carrying oncogenic RAS.

4-Methylesculetin (Methylesculetin) is one of the coumarin derivatives with great anti-oxidant and anti-inflammatory activities.

ML162 is an inhibitor of GPX4 that is selectively lethal to mutant RAS oncogene-expressing cell lines (IC50s = 25 and 578 nM for HRASG12V-expressing and wild-type BJ fibroblasts, respectively)

ML-210 (CID 49766530) is a selective RAS and covalent glutathione peroxidase 4 (GPX4) inhibitor(GPX4, EC50 : 30 nM), with anti-cancer activity

Ebselen (CCG-39161) is a organoselenium compound with anti-inflammatory, anti-oxidant and cytoprotective activity. Ebselen acts as a glutathione peroxidase mimetic and is thereby able to prevent cellular damage induced by reactive oxygen species (ROS). In addition, this agent inhibits the activity of a variety of enzymes including nitric oxide synthase (NOS), 5-lipoxygenase, cyclooxygenase, protein kinase C (PKC), NADPH oxidase and gastric H+/K+-ATPase. Furthermore, ebselen may be neuroprotective due to its ability to neutralize free radicals upon NMDA receptor activation thus, reducing lipoperoxidation mediated by glutamate-induced excitotoxicity.

PF-06282999 is a potent and selective myeloperoxidase inhibitor which is potentially useful for the treatment of cardiovascular diseases.

RC363 is an inhibitor of ferroptosis and a derivative of the antioxidant and hypocholesterolemic agent probucol .1It reduces 2,2-diphenyl-1-picrylhydrazyl radicals by approximately 40% in a cell-free assay when used at a concentration of 25 μM. RC363 prevents glutamate-induced toxicity in HT22 cultured hippocampal cells (IC50= 234.5 nM) but does not reduce oxidant levels in these cells. It increases the levels of glutathione peroxidase 1 (GPX1) and the activity of GPX in glutamate-challenged HT22 cells when used at a concentration of 3 μM. RC363 inhibits ferroptosis induced by the GPX4 inhibitor RSL3 in HT22 cells (IC50= 173.6 nM). 1.Bueno, D.C., Canto, R.F.S., de Souza, V., et al.New probucol analogues inhibit ferroptosis, improve mitochondrial parameters, and induce glutathione peroxidase in HT22 cellsMol. Neurobiol.57(8)3273-3290(2020)

Verdiperstat (AZD 3241) is a selective, irreversible and orally active myeloperoxidase inhibitor, with an IC50 of 630 nM, and can be used in the research of neurodegenerative brain disorders.

MPO-IN-28 is a novel potent, irreversible Myeloperoxidase (MPO) inhibitor with IC50 of 44 nM.

(E)-2-(2-Chlorostyryl)-3,5,6-trimethylpyrazine (CSTMP) is a stilbene derivative with antioxidant and anticancer activities. It stimulates proliferation of hydrogen peroxide-damaged ECV-304 cells (EC50 = 24.9 nM). CSTMP reduces hydrogen peroxide-induced release of lactate dehydrogenase (LDH) in and increases viability of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner via inhibition of apoptosis. It reverses hydrogen peroxide-induced release of malondialdehyde (MDA) and decreases in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities as well as increases constitutive nitric oxide synthase (cNOS) activity and nitric oxide (NO) production in HUVECs. CSTMP also induces cell death of A549 non-small cell lung cancer (NSCLC) cells in an IRE1α-dependent manner through induction of IRE1α-TRAF2-ASK1 complex-mediated endoplasmic reticulum (ER) stress and mitochondrial apoptosis.

3-Amino-1,2,4-triazole (Trapidil impurity B) is an inhibitor of catalase, capable of inducing the compensatory mechanism for hydrogen peroxide detoxification. This mechanism involves increasing the activities of glutathione peroxidase and glutathione reductase.

NBDHEX is a potent inhibitor of glutathione S-transferase P1-1 (GSTP1-1) .

GPX4-IN-3 (26a) is a potent inhibitor of glutathione peroxidase 4 (GPX4), selectively inducing ferroptosis. It demonstrates a 71.7% inhibition rate of GPX4 at a concentration of 1 μM [1].

Gamma-glutamylcysteine (TFA) ((γ-glutamylcysteine (TFA)), a crucial dipeptide in glutathione (GSH) synthesis and a vital cofactor for the enzyme glutathione peroxidase (GPx), significantly modulates inflammatory responses. It enhances the level of the anti-inflammatory cytokine IL-10, diminishes the concentrations of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), and mitigates alterations in metalloproteinase activity in oligomeric Aβ40-treated astrocytes.

L-SelenoMethionine (L-(+)-Selenomethionine) is a naturally occurring amino acid. It promotes cell cycle progression and elevates the expression of the antioxidant enzymes thioredoxin reductase, glutathione reductase.

4-POBN (Myeloperoxidase Inhibitor 1) is a potent and irreversible inhibitor of myeloperoxidase (IC50 = 0.3 µM). 4-POBN can be used in studies about subacute stroke.

Spirotetramat is an insecticide that demonstrates efficacy against C. pyrinymphs in vitro (LC50= 6.51-12.53 mg AI/L) and achieves a 99.2% mortality rate in C. pyrinymphs within European pear (P. communis) fields 15 days post-application at a dosage of 27 g/hectare. Additionally, it reduces embryonic viability and nymph survival in O. insidiosus. Spirotetramat exhibits aquatic toxicity by altering protein levels in organisms, specifically by increasing glutathione peroxidase (GPX) and superoxide dismutase (SOD) levels, decreasing malondialdehyde (MDA) levels, and causing lethality in Chinese toad (B. gargarizans) tadpoles (LC50= 6.98 mg/L). Its formulations are utilized in agricultural insect control. Spirotetramat is marketed exclusively for research and analytical applications, formulated for controlled laboratory settings without the availability of bulk sizes.

RC574 is an inhibitor of ferroptosis and a derivative of the antioxidant and hypocholesterolemic agent probucol .1It inhibits glutamate-induced cell death in HT22 cells (IC50= 276.2 nM) and mouse primary cortical neurons when used at a concentration of 3 μM. RC574 (3 μM) increases glutathione peroxidase 1 (GPX1) levels and GPX activity, as well as inhibits glutamate-induced mitochondrial superoxide anion production, in HT22 cells. It completely inhibits ferroptosis induced by the GPX4 inhibitor RSL3 in HT22 cells when used at concentrations ranging from 62.5 to 1,000 nM. 1.Bueno, D.C., Canto, R.F.S., de Souza, V., et al.New probucol analogues inhibit ferroptosis, improve mitochondrial parameters, and induce glutathione peroxidase in HT22 cellsMol. Neurobiol.57(8)3273-3290(2020)

PKUMDL-LC-101-D04 is a potent allosteric activator of glutathione peroxidase 4 (GPX4), a regulator of ferroptosis. GPX4 activity was increased to 150% of control levels when used at a concentration of 20 μM in a cell-free assay, and at a concentration of 61 μM in wild-type, but not Gpx4-/-, mouse embryonic fibroblast (MEF) extracts.PKUMDL-LC-101-D04 (200 μM) reduced cholesterol peroxide-induced MEF death.

AZD5904 is a potent and irreversible human Myeloperoxidase (MPO) inhibitor(IC50 of 140 nM and has similar potency in mouse and rat).

3-Deoxyglucosone(3-Deoxy-D-glucosone) is synthesized by the intermediate pathway of the melad and polyol reactions.3-Deoxyglucosone reacts rapidly with protein amino groups to form advanced glycosylated end proteins (AGEs).3-Deoxyglucosone inactivates glutathione peroxidase and synergizes with low glucose to enhance GLP-1 secretion.3-Deoxyglucosone is used as a biomarker for diabetes mellitus.3-Deoxyglucosone has been shown to be an inhibitor of GLP-1 secretion in the presence of low glucose. 3-Deoxyglucosone inactivates glutathione oxidase, synergizes with low glucose to enhance GLP-1 secretion, and can be used as a biologic marker for diabetes.

JKE-1716 is an inhibitor of glutathione peroxidase 4 (GPX4) and a derivative of the GPX4 inhibitor ML-210 .1JKE-1716 reduces viability of LOX-IMVI cancer cells in a concentration-dependent manner and in a panel of additional cancer cell lines, an effect that can be blocked by the ferroptosis inhibitor ferrostatin-1 . 1.Eaton, J.K., Furst, L., Ruberto, R.A., et al.Selective covalent targeting of GPX4 using masked nitrile-oxide electrophilesNat. Chem. Biol.16(5)497-506(2020)

Tinoridine hydrochloride (Y-3642 hydrochloride) is a non-steroidal anti-inflammatory drug. Tinoridine hydrochloride (5-100 μM), produced a concentration-dependent inhibition on the simultaneous increases in lipid peroxide formation and renin release induced by 50 μM ascorbic acid in the renin granule fraction. On the other hand, indomethacin, hydrocortisone, and prednisolone, which had no ability to inhibit the lipid peroxidation in the renin granule fraction, did not influence the release of renin from the granules. These results suggest that tinoridine suppresses renin release by inhibiting the oxidative disintegration of membranes of renin granules.